Sulphonylbenzyl-substituted imidazolylpropenoic acid derivatives

ABSTRACT

Sulphonylbenzyl-substituted imidazolylpropenoic acid derivatives can be prepared by reacting sulphonylbenzyl-substituted aldehydes with appropriate CH-acidic compounds and then dehydrating. 
     The sulphonylbenzyl-substituted imidazolylpropenoic acid derivatives can be used in medicaments, in particular for the treatment of high blood pressure and atherosclerosis.

This application is a or divisional, of application Ser. No. 08/019,001,filed Feb. 18, 1993, now U.S. Pat. No. 5,475,016.

The present invention relates to sulphonylbenzyl-substitutedimidazolylpropenoic acid derivatives, to a process for their preparationand to their use in medicaments, in particular as hypotensive andanti-atherosclerotic agents.

It is known that renin, a proteolytic enzyme, cleaves the decapeptideangiotensin I in vivo from angiotensinogen, which is in turn degraded inthe lungs, the kidneys or other tissues to give the hypertensiveoctapeptide angiotensin II. The various effects of angiotensin II, suchas, for example, vasoconstriction, Na⁺ retention in the kidney,aldosterone release in the adrenal gland and increase in tone of thesympathetic nervous system, act synergistically in the sense of a bloodpressure increase.

Moreover, angiotensin II has the property of promoting the growth andthe replication of cells such as, for example, of cardiac muscle cellsand smooth muscle cells, these growing and proliferating in an increasedmanner in various disease states (for example hypertension,atherosclerosis and cardiac insufficiency).

In addition to the inhibition of renin activity, a possible startingpoint for intervention in the renin-angiotensin system (RAS) is theinhibition of the activity of angiotensin-converting enzyme (ACE) andthe blockade of angiotensin II receptors.

The publications EP 324,377 A2, EP 403,158 A2 and EP 403,159 A2 describephenyl (alkyl) imidazole- and imidazolylalkenoic acids.

The present invention relates to compounds of the general formula (I)##STR1## in which R¹ represents straight-chain or branched alkyl oralkenyl each having up to 8 carbon atoms, each of which is optionallysubstituted by cycloalkyl having 3 to 6 carbon atoms, or representscycloalkyl having 3 to 8 carbon atoms,

R² represents hydrogen, halogen or straight-chain or branchedperfluoroalkyl having up to 8 carbon atoms,

n represents a number 0, 1, 2, 3 or 4

R³ represents hydrogen or represents straight-chain or branched alkylhaving up to 8 carbon atoms, represents a 5- to 7-membered, saturated orunsaturated heterocycle having up to 2 further hereto atoms from theseries consisting of S, N and O, or represents aryl having 6 to 10carbon atoms, or represents cycloalkyl having 3 to 8 carbon atoms, wherethe cycles are optionally substituted up to 2 times by identical ordifferent substituents from the group consisting of halogen, hydroxyl,nitro, cyano, trifluoromethyl and trifluoromethoxy or by straight-chainor branched alkyl or alkoxy each having up to 8 carbon atoms,

R⁴ represents hydroxyl, straight-chain or branched alkoxy having up to 8carbon atoms, phenoxy or a group of the formula --NR⁶ R⁷

in which

R⁶ and R⁷ are identical or different and denote hydrogen orstraight-chain or branched alkyl having up to 6 carbon atoms or phenyl,

R⁵ represents hydrogen, halogen or straight-chain or branched alkylhaving up to 8 carbon atoms, or represents straight-chain or branchedperfluoroalkyl having up to 6 carbon atoms, or

represents a group of the formula --OX,

in which

X denotes hydrogen, benzyl, a hydroxyl protective group or denotesstraight-chain or branched alkyl having up to 8 carbon atoms

A represents a 3- to 8-membered, saturated heterocycle bonded via thenitrogen atom and having up to 2 further hetero atoms from the seriesconsisting of S, N and O and which is optionally substituted up to 2times by identical or different perfluoroalkyl having up to 5 carbonatoms or by a radical of the formula ##STR2## in which R⁸ denoteshydrogen, straight-chain or branched alkyl having up to 6 carbon atomsor triphenylmethyl

R⁹ has the abovementioned meaning of R⁴ and is identical to or differentfrom this and

R¹⁰ and R¹¹ are identical or different and denote hydrogen,straight-chain or branched alkyl having up to 8 carbon atoms or phenyl,and their salts.

The sulphonylbenzyl-substituted imidazolylpropenoic acid derivativesaccording to the invention can also be present in the form of theirsalts. In general, salts with organic or inorganic bases or acids may bementioned here.

In the context of the present invention, physiologically acceptablesalts are preferred. Physiologically acceptable salts of thesulphonylbenzyl-substituted imidazolylpropenoic acid derivatives can besalts of the substances according to the invention with mineral acids,carboxylic acids or sulphonic acids. Particularly preferred salts are,for example, those with hydrochloric acid, hydrobromic acid, sulphuricacid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid,toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonicacid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid,tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts ofthe compounds according to the invention which have a free carboxylgroup. Particularly preferred salts are, for example, sodium, potassium,magnesium or calcium salts, and also ammonium salts which are derivedfrom ammonia or organic amines such as, for example, ethylamine, di- ortriethylamine, di- or triethanolamine, dicyclohexylamine,dimethylaminoethanol, arginine, lysine or ethylenediamine.

The compounds according to the invention can exist in stereoisomericforms, either as enantiomers or as diastereomers. The invention relatesboth to the enantiomers or diastereomers and their respective mixtures.The racemic forms, like the diastereomers, can be separated in a knownmanner into the stereoisomerically uniform constituents [cf. E. L.Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962].

Preferred compounds of the general formula (I) are those

in which

R¹ represents straight-chain or branched alkyl or alkenyl each having upto 6 carbon atoms, each of which is optionally substituted bycyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, representscyclopropyl, cyclopentyl or cyclohexyl,

R² represents hydrogen, fluorine, chlorine, bromine or straight-chain orbranched perfluoroalkyl having up to 6 carbon atoms,

n represents a number 0, 1, 2 or 3

R³ represents hydrogen or represents straight-chain or branched alkylhaving up to 6 carbon atoms,

represents thienyl, phenyl, cyclopropyl, cyclopentyl, cyclohexyl orcycloheptyl, which are optionally substituted up to 2 times by identicalor different substituents from the group consisting of fluorine,chlorine, bromine, hydroxyl, nitro, cyano, trifluoromethyl andtrifluoromethoxy or by straight-chain or branched alkyl or alkoky eachhaving up to 6 carbon atoms,

R⁴ represents hydroxyl, straight-chain or branched alkoxy having up to 6carbon atoms, phenoxy or a group of the formula --NR⁶ R⁷,

in which

R⁶ and R⁷ are identical or different and denote hydrogen orstraight-chain or branched alkyl having up to 4 carbon atoms,

R⁵ represents hydrogen, fluorine, chlorine, bromine, straight-chain orbranched alkyl having up to 6 carbon atoms, or represents straight-chainor branched perfluoroalkyl having up to 4 carbon atoms, or

represents a group of the formula --OX, in which

X denotes hydrogen, benzyl, acetyl or straight-chain or branched alkylwith up to 6 cubon morns

A represents piperidyl, pyrrolidinyl or morpholinyl bonded via thenitrogen atom, which are optionally substituted by trifluoromethyl or bya radical of the formula ##STR3## in which R⁸ denotes hydrogen,straight-chain or branched alkyl having up to 4 carbon atoms ortriphenylmethyl

R⁹ has the abovementioned meaning of R⁴ and is identical to or differentfrom this and

R¹⁰ and R¹¹ are identical or different and denote hydrogen orstraight-chain or branched alkyl having up to 6 carbon atoms or phenyl,

and their salts.

In addition, a process for the preparation of the compounds of thegeneral formula (I) according to the invention has been found,characterised in that aldehydes of the general formula (II) ##STR4## inwhich R¹, R², R⁵ and A have the abovementioned meaning,

are first converted by reaction with CH-acidic compounds of the generalformula (III)

    R.sup.3 --(CH.sub.2).sub.n --CH.sub.2 --CO.sub.2 --R.sup.12(III)

in which

R³ and n have the abovementioned meaning and

R¹² has the abovementioned meaning of R⁴, but does not representhydrogen,

in inert solvents, in the presence of a base, to give the compounds ofthe general formula (IV) ##STR5## in which R¹, R², R³, R⁵, R¹² and Ahave the abovementioned meaning,

then the free hydroxyl function is blocked by introduction of aprotective group and in a last step an elimination in inert solvents inthe presence of a base is carried out,

and in the case of the acids (R⁴ ═OH) the esters are hydrolysed

and in the case in which R⁸ does not represent hydrogen, the --NHfunction is alkylated.

The process according to the invention can be illustrated by way ofexample by the following reaction scheme: ##STR6##

Hydroxyl protective group in the context of the abovementioneddefinition in general represents a protective group from the seriescomprising: benzyloxycarbonyl, methanesulphonyl, toluenesulphonyl,2-nitrobenzyl, 4-nitrobenzyl, 2-nitrobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl,4-methoxycarbonyl, acetyl, trichloroacetyl,2,2,2-trichloroethoxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,2-(methylthiomethoxy)ethoxycarbonyl, benzoyl, 4-methylbenzoyl,4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl or 4-methoxybenzoyl.Acetyl, methanesulphonyl and toluenesulphonyl are preferred.

Suitable solvents for the process are the customary organic solventswhich do not change under the-reaction conditions. These preferablyinclude ethers such as diethyl ether, dioxane, tetrahydrofuran, glycoldimethyl ether, and hydrocarbons such as benzene, toluene, xylene,hexane, cyclohexane or mineral oil fractions, and halogenohydrocarbonssuch as dichloromethane, trichloromethane, tetrachloromethane,dichloroethylene, trichloroethylene or chlorobenzene, and ethyl acetate,triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide,hexamethylphosphoric triamide, acetonitrile, acetone and nitromethane.It is also possible to use mixtures of the solvents mentioned.Tetrahydrofuran, methylene chloride and toluene are preferred for thevarious steps.

Bases which can be employed for the process according to the inventionare in general inorganic or organic bases.

These preferably include alkali metal hydroxides such as, for example,sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxidessuch as, for example, barium hydroxide, alkali metal carbonates such assodium carbonate or potassium carbonate, alkaline earth metal carbonatessuch as calcium carbonate, and alkali metal or alkaline earth metalalkoxides or amides such as sodium methoxide or potassium methoxide,sodium ethoxide or potassium ethoxide or potassium tert-butoxide orlithium diisopropylamide (LDA), and organic amines (trialkyl-(C₁-C₆)amines) such as triethylamine or N,N-diisopropylamine, andheterocycles such as 1,4-diazabicyclo[2.2.2]-octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine,methylpiperidine or morpholine. It is also possible to employ as basesalkali metals, such as sodium, or their hydrides such as sodium hydride.Sodium hydride, lithium diisopropylamide (LDA), DBU andN,N-diisopropylamine are preferred.

In general, the base is employed in an amount from 0.05 mol to 10 mol,preferably from 1 mol to 2 mol, relative to 1 mol of the compound of theformula (III).

The process according to the invention is in general carried out in atemperature range from -100° C. to +100° C., preferably at -78° C.

The process according to the invention is in general carried out atnormal pressure. However, it is also possible to carry out the processat elevated pressure or at reduced pressure (for example in a range from0.5 to 5 bar).

The introduction of the protective group is in general, carried out inone of the abovementioned solvents and a base, preferably in methylenechloride using dimethylaminopyridine.

The blocking is in general carried out in a temperature range from 0° C.to +60° C., preferably at room temperature and at normal pressure.

The elimination is in general carried out in one of the abovementionedsolvents, preferably in toluene and in the presence of one of the basesmentioned, preferably DBU.

The elimination is in general carried out in a temperature range from+30° C. to +130° C., preferably at +50° C. to +100° C. and at normalpressure.

Suitable bases for the hydrolysis are the customary inorganic bases.These preferably include alkali metal hydroxides and alkaline earthmetal hydroxides such as, for example, sodium hydroxide, potassiumhydroxide or barium hydroxide, and alkali metal carbonates such assodium carbonate or potassium carbonate or sodium hydrogen carbonate andalkali metal alkoxides such as sodium methoxide, sodium ethoxide,potassium methoxide, potassium ethoxide or potassium tert-butoxide.Sodium hydroxide or potassium hydroxide is particularly preferablyemployed.

Suitable solvents for the hydrolysis are water or the organic solventscustomary for hydrolysis. These preferably include alcohols such asmethanol, ethanol, propanol, isopropanol or butanol, and ethers such astetrahydrofuran or dioxane, and dimethylformamide, and dimethylsulphoxide. Particularly preferably, alcohols such as methanol, ethanol,propanol or isopropanol are used. It is also possible to employ mixturesof the solvents mentioned.

The hydrolysis can also be carried out using acids such as, for example,trifluoroacetic acid, acetic acid, hydrochloric acid, hydrobromic acid,methanesulphonic acid, sulphuric acid or perchloric acid, preferablyusing trifluoroacetic acid.

The hydrolysis is in general carried out in a temperature range from 0°C. to +100° C. preferably from +20° C. to +80° C.

In general, the hydrolysis is carried out at normal pressure. However,it is also possible to work at reduced pressure or at elevated pressure(for example from 0.5 to 5 bar).

When carrying out the hydrolysis, the base is in general employed in anamount from 1 to 3 mol, preferably from 1 to 1.5 mol, relative to 1 molof the ester. Particularly preferably, molar amounts of the reactantsare used.

When carrying out the reaction, in the first step the carboxylates ofthe compounds according to the invention are formed as intermediateswhich can be isolated. The acids according to the invention are obtainedby treating, the carboxylates with customary inorganic acids. Thesepreferably include mineral acids such as, for example, hydrochloricacid, hydrobromic acid, sulphuric acid or phosphoric acid. It has provedadvantageous in the preparation of the carboxylic acids in thisconnection to acidify the basic reaction mixture from the hydrolysis ina second step without isolation of the carboxylates. The acids can thenbe isolated in a customary manner. In the case of the basicheterocycles, by treatment of the solutions of the carboxylates with theabovementioned acids the salts of the heterocycles with the inorganicacids can also be obtained.

The alkylation is in general carried out using alkylating agents suchas, for example, (C₁ -C₆)-alkyl halides, sulphonic acid esters orsubstituted or unsubstituted (C₁ -C₆)-dialkyl or (C₁ -C₆)-diarylsulphates, preferably methyl iodide or dimethyl sulphate.

The alkylation is in general carried out in one of the abovementionedsolvents, preferably in dimethylformamide, in a temperature range from0° C. to +70° C., preferably from 0° C. to +30° C. and at normalpressure.

The aldehydes of the general formula (II) are also new and can beprepared by reacting imidazoles of the general formula (V) ##STR7## inwhich R¹ and R² have the abovementioned meaning,

with compounds of the general formula (VI) ##STR8## in which R⁵ and Ahave the abovementioned meaning and

W represents halogen, preferably bromine,

in one of the abovementioned solvents in the presence of one of thebases mentioned there, preferably in dimethyl-formamide, using sodiumhydride.

The compounds of the general formula (VI) are new and can be prepared byreacting substituted benzylsulphonyl chlorides of the general formula(VII) ##STR9## in which W and R⁵ have the abovementioned meaning

with compounds of the general formula (VIII)

    H-A                                                        (VIII),

in which

A has the abovementioned meaning,

in one of the abovementioned solvents and bases, preferably indichloromethane, using triethylamine,

The reaction is in general carried out in a temperature range from 0° C.to +100° C., preferably from +20° C. to +80° C.

In general, the reaction is carried out at normal pressure. However, itis also possible to work at reduced pressure or at elevated pressure(for example from 0.5 to 5 bar).

When carrying out the reaction, the base is in general employed in anamount from 1 to 3 mol, preferably from 1 to 1.5 mol, relative to 1 molof the compounds of the general formulae (V) and (VII). Molar amounts ofthe reactants are particularly preferably used.

The reaction is in general carried out in a temperature range from -10°C. to +40° C., preferably from -10° C. to 0° C., and under normalpressure.

The compounds of the general formulae (VII) and (VIII) are known or canbe prepared by a customary method.

The CH-acidic compounds of the general formula (III) are known or can beprepared by a customary method [cf., for example, Beilstein 9,511].

The compounds of the general formula (IV) are also new and can beprepared by the abovementioned process.

The compounds of the general formula (I) according to the inventionexhibit an unforeseeable, useful pharmacological spectrum of action.

The compounds according to the invention have a specific AII-antagonistic action, since they competitively inhibit the binding ofangiotensin II to A II receptors. They suppress the vasoconstrictory andaldosterone secretion-stimulating effects of angiotensin II. Moreover,they inhibit the proliferation of smooth muscle cells.

They can therefore be employed in medicaments for the treatment ofarterial hypertension and atherosclerosis. Moreover, they can be usedfor the treatment of coronary heart diseases, cardiac insufficiency,disorders of cerebral function, ischaemic brain disorders, peripheralcirculatorydisorders, functional disorders of the kidney and adrenalgland, bronchospastic and vascularly conditioned disorders of theairways, sodium retention and oedemas.

Moreover, the substances have natriuretic and diuretic action. Thisaction is manifested in a mobilisation of oedema fluid with an increasein pathological fluid of cardiac and non-cardiac origin.

Investigation of the Inhibition of the Contraction Induced with Agonists

Rabbits of both sexes are anaesthetised by a blow to the neck and bledout, or alternatively anaesthetised with Nembutal (about 60-80 mg/kgi.v.) and sacrificed by opening the thorax. The thorax aorta is takenout, freed from adhering connective tissue, divided into 1.5 mm-widering segments and these are individually transferred under an initialloading of about 3.5 g to 10-ml organ baths containing 95% O₂ /5% CO₂-aerated Krebs-Henseleit nutrient solution, thermostated at 37° C., ofthe following composition: 119 mmol/l NaCl; 2.5 mmol/l CaCl₂ ×2H₂ O; 1.2mmol/l KH₂ PO₄ ; 10 mmol/l glucose; 4.8 mmol/l KCl; 1.4 mmol/l MgSO₄ ×7H₂ O and 25 mmol/l NaHCO₃.

The contractions are detected isometrically by Statham UC2 cells bymeans of a bridge amplifier (ifd Mulheim or DSM Aalen) and digitised andevaluated by means of an A/D converter (System 570, Keithley, Munich).The implementation of agonist dose-response curves (DRC) is carried outhourly. With each DRC, 3 or 4 individual concentrations are applied tothe baths at 4-min intervals. After the end of the DRC and subsequentwashing-out cycles (16 times, in each case about 5 sec/min with theabovementioned nutrient solution), a 28-minute rest or incubation phasefollows, in the course of which the contractions as a rule reach thestarting value again.

The height of, in the normal case, the 3rd DRC is used as a referencequantity for the assessment of the test substance to be investigated infurther runs, which test substance in the following DRCs is applied atthe start of the incubation time to the baths, in each case in anincreasing dose. Each aorta ring is in this case stimulated for thewhole day, always with the same agohist.

    ______________________________________                                        Agonists and their standard concentrations (admini-                           stration volume per individual dose = 100 μl);                             ______________________________________                                        KCl      22.7; 32.7; 42.7; 52.7  mmol/l                                       1-Noradrena-                                                                           3 × 10.sup.-9 ; 3 × 10.sup.-8 ; 3 × 10.sup.-7               ; 3 × 10.sup.-6   g/ml                                         line                                                                          Serotonin                                                                              10.sup.-8 ; 10.sup.-7 ; 10.sup.-6 ; 10.sup.-5                                                         g/ml                                         B-HT 920 10.sup.-7 ; 10.sup.-6 ; 10.sup.-5                                                                     g/ml                                         Methoxamine                                                                            10.sup.-7 ; 10.sup.-6 ; 10.sup.-5                                                                     g/ml                                         Angiotensin                                                                            3 × 10.sup.-9 ; 10.sup.-8 ; 3 × 10.sup.-8 ;                       10.sup.-7               g/ml                                         II                                                                            ______________________________________                                    

For the calculation of the IC₅₀ (concentration at which the substance tobe investigated causes a 50% inhibition), the effect in each case at the3rd=submaximal agonist concentration is used as a basis.

The compounds according to the invention inhibit the contraction of theisolated rabbit aorta induced by angiotensin II in a dose-dependentmanner. The contraction induced by potassium depolarisation or otheragonists was not inhibited, or only weakly inhibited at highconcentrations.

                  TABLE A                                                         ______________________________________                                        Inhibition of the vascular contraction in isolated aorta                      rings of rabbits in vitro                                                     IC.sub.50 [nM] against contractions induced by:                               Ex. No.:     AII IC.sub.50 [nM]                                               ______________________________________                                        19           40                                                               2            11                                                               39           4                                                                55           3                                                                24           1                                                                43           3                                                                47           4                                                                53           6                                                                57           6                                                                ______________________________________                                    

Blood Pressure Measurements on the Angiotensin II-Infused Rat

Male Wistar rats (Moellegaard, Copenhagen, Denmark) having a body weightof 300-350 g are anaesthetised with thiopental (100 mg/kg i.p.). Aftertracheotomy, a catheter is inserted in the femoral artery for bloodpressure measurement and a catheter for angiotensin II infusion and acatheter for substance administration are inserted in the femoral veins.After administration of the ganglionic blocker pentolinium (5 mg/kgi.v.), the angiotensin II infusion (0.3 μg/kg/min) is started. As soonas the blood pressure values have reached a stable plateau, the testsubstances are administered either, intravenously or orally as asuspension or solution in 0.5% Tylose. The blood pressure changes underthe influence of substance are indicated in the table as average values±SEM.

                  TABLE B                                                         ______________________________________                                                               Blood Pressure                                         Ex. No.:     mg/kg p.o.                                                                              measurement                                            ______________________________________                                        23           0.1       -17 mm HG                                              24                                                                            43           0.1       -10 mm Hg                                              47                                                                            41           0.1       -11 mm Hg                                              53                                                                            57                                                                            ______________________________________                                    

Determination of the Antihypertensive Activity in Conscious HypertensiveRats

The oral antihypertensive activity of the compounds according to theinvention was tested on conscious rats having surgically inducedunilateral renal artery stenosis. For this, the right renal artery wasconstricted with a silver clip of 0.18-mm internal width. In this formof hypertension, the plasma renin activity is increased in the first sixweeks after intervention. The arterial blood pressure of these animalswas measured by bloodless means at defined time intervals aftersubstance administration using the "tail cuff". The substances to betested were administered intragastrally ("orally") by stomach tube indifferent doses, suspended in a Tylose suspension. The compoundsaccording to the invention lower the arterial blood pressure of thehypertensive rats at a clinically relevant dosage.

In addition, the compounds according to the invention inhibit thespecific binding of radioactive angiotensin II in aconcentration-dependent manner.

Interaction of the Compounds According to the Invention with theAngiotensin II Receptor on Membrane Fractions of the Adrenal GlandCortex (Cattle)

Adrenal gland cortices of cattle (AGC), which have been freshly removedand carefully freed from gland medulla, are comminuted in sucrosesolution (0.32M) with the aid of an Ultra-Turrax (Janke & Kunkel,Staufen i.B.) to give a coarse membrane homogenate and are partiallypurified in two centrifugation steps to give membrane fractions. Thereceptor binding investigations are carried out on partially purifiedmembrane fractions of bovine AGC using radioactive angiotensin II in anassay volume of 0.25 ml, which in detail contains the partially purifiedmembranes (50-80 μg), ³ H-angiotensin II (3-5 nM), test buffer solution(50 mM tris, pH 7.2, 5 mM MgCl₂, 0.25% BSA) and the substances to beinvestigated. After an incubation time of 60 min at room temperature,the unbound radioactivity of the samples is separated by means ofmoistened glass fibre filters (Whatman GF/C) and the bound radioactivityis measured spectrophotometrically in a scintillation cocktail afterwashing the protein with ice-cold buffer solution (50 mM tris/HCl, pH7.4, 5% PEG 6000). The analysis of the raw data was carried out usingcomputer programs to give K_(i) or IC₅₀ values (K_(i) : IC₅₀ valuescorrected for the radioactivity used; IC₅₀ values: concentration atwhich the substance to be investigated causes a 50% inhibition of thespecific binding of the radioligand).

Ex. 9 Ki=100 nM

Ex. 10 Ki=40 nM

Ex. 20 Ki=40 nM

Ex. 30 Ki=120 nM

Investigation of Inhibition of the Proliferation of Smooth Muscle Cellsby the Compounds According to the Invention

To determine the antiproliferative action of the compounds, smoothmuscle cells are used which have been obtained from the aortas of ratsor pigs by the media explant technique [R. Ross, J. Cell. Biol. 50, 172,1971]. The cells are inoculated into suitable culture dishes, as a rule24-hole plates, and cultured at 37° C. in 5% CO₂ for 2-3 days in Medium199 containing 7.5% FCS and 7.5% NCS, 2 mM L-glutamine and 15 mM HEPES,pH 7.4. After this, the cells are synchronised by withdrawal of serumfor 2-3 days and then stimulated into growth with AII, serum or otherfactors. At the same time, test compounds are added. After 16-20 hours,1 μCi of ³ H-thymidine is added and the incorporation of this substanceinto the TCA-precipitable DNA of the cells is determined after a further4 hours.

    ______________________________________                                        Example No.  % inihibition at 10.sup.-6 M                                     ______________________________________                                        6            70                                                               7            30                                                               ______________________________________                                    

Test for Naurrivretic Effect

Fasting Wistar rats are treated orally with test substance (suspended inTylose solution). The urine excretion is then collected in diuresiscages over the course of 6 hours. The concentration of sodium andpotassium in the urine is determined by flame photometry.

The new active substance can be converted in a known manner into thecustomary formulations, such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, nontoxic, pharmaceutically suitable excipients or solvents. Thetherapeutically active compound should in each case be present in aconcentration of about 0.5 to 90% by weight of the total mixture, i.e.in amounts which are sufficient in order to achieve the dosage rangeindicated.

The formulations are prepared, for example, by extending the activesubstances with solvents and/or excipients, if appropriate usingemulsifiers and/or dispersants, where, for example, in the case of theuse of water as a diluent, organic solvents can be used as auxiliarysolvents if appropriate.

Administration is carried out in a customary manner, preferably orallyor parenterally, in particular per-lingually or intravenously.

In the case of parenteral administration, solutions of the activesubstance using suitable liquid excipients can be employed.

In general, it has proved advantageous on intravenous administration toadminister amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to0.5 mg/kg of body weight to achieve effective results, and on oraladministration the dosage is about 0.01 to 20 mg/kg, preferably 0.1 to10 mg/kg of body weight.

In spite of this, it may be necessary to depart from the amountsmentioned, in particular depending on the body weight or the type ofadministration route, on individual behaviour towards the medicament,the manner of its formulation and the time or interval at whichadministration takes place. Thus, in some cases, it may be sufficient tomanage with less than the abovementioned minimum amount, while in othercases the upper limit mentioned must be exceeded. In the case of theadministration of larger amounts, it may be advisable to divide theseinto several individual doses over the course of the day.

Mobile phase mixtures:

a=methylene chloride/methanol 20:1

b=methylene chloride/methanol 10:1

c=methylene chloride/ethyl acetate 15:1

d=methylene chloride/ethyl acetate 10:1

e=methylene chloride/ethyl acetate 30:1

f=toluene/ethyl acetate/acetic acid=20:20:1

STARTING COMPOUNDS EXAMPLE I 4-(Bromomethyl)bnzene-sulphochloride##STR10##

38.1 g (0.2 mol) of 4-methylbenzenesulphonyl chloride are dissolved in300 ml of carbon tetrachloride and treated with 35.6 g (0.2 mol) ofN-bromosuccinimide and, after addition of 0.2 g (1.2 mmol) ofazobisisobutyronitrile (ABU), the mixture is heated under reflux for 4h. After cooling, the solids are filtered off and the filtrate is freedfrom the solvent. Flash chromatography (petroleum ether/toluene 4:1, 50μm particle size) and subsequent recrystallisation from 100 ml ofcyclohexane gives 24.0 g (45% of theory) of the title compound. R_(f)=0.75 (toluene)

EXAMPLE II 4-(Bromomethyl)-3-chlorobenzenesulphochloride ##STR11##

45.9 g (0.2 mol) of sodium 3-chloro-4-methylbenzenesulphonate are mixedwith 83.3 g (0.4 mol) of phosphorus pentachloride and heated for 30 minat an oil bath temperature of 140° C. The hot mixture is treated with500 ml of toluene, and the resulting solution is heated to boiling and,after cooling, poured onto ice. The organic phase is separated off andwashed with water (2×200 ml). After drying over MgSO₄, it is filteredand all the volatiles are stripped off in vacuo. The residue obtained ispurified by flash chromatography (petroleum ether/toluene 4:1, 50 μmparticle size). 24.9 g of a product are obtained which is immediatelyreacted further:

It is taken up in 200 ml of carbon tetrachloride and, after addition of19.6 g (0.11 mol) of N-bromosuccinimide and 0.1 g (0.6 mmol) of ABN,heated under reflux for 6 h. After cooling, the solids are filtered offand the filtrate is freed from solvent. Flash chromatography (petroleumether/toluene 4:1, 50 μm particle size) gives 21.2 g (35%) of the titlecompound. R_(f) =0.32 (petroleum ether/dichloromethane 4:1)

EXAMPLE III 5 4-(Bromomethyl)-benzenesulphonyl-N-pyrrolidinide ##STR12##

5.3 g (0.02 mol) of the compound from Example III are dissolved in 200ml of dichloromethane and 4.0 g (0.04 mol) of triethylamine and, afteraddition of 1.4 g (0.02 mol) of pyrrolidine, the mixture is stirred at0° C. for 1 h in 50 ml of dichloromethane. The mixture is extracted with2N HCl (2×100 ml), H₂ O (2×100 ml), dried over MgSO₄ and filtered, andall the volatile components are evaporated in vacuo.

Yield: 5.4 g (89% of theory)

R_(f) =0.09 (toluene)

EXAMPLE IV 4-(Bromomethyl)-benzenesulphonyl-N-piperidinide ##STR13##

In analogy to the procedure of Example III, 1.0 g (81% of theory) of thetitle compound is obtained from 1.1 g (4 mmol) of the compound fromExample III and 0.34 g (4 mmol) of piperidine.

R_(f) =0.14 (toluene)

EXAMPLE V(S)-4-(Bromomethyl)-benzenesulphonyl-N-2-(tert-butoxycarbonyl)pyrrolidinide##STR14##

In analogy to the procedure of Example III, 9.1 g (84% of theory) of thetitle compound are obtained from 7.25 g (27 mmol) of the compound fromExample III and 4.6 g (27 mmol) of S-proline tert-butyl ester.

Rf=0.66 (petroleum ether/ethyl acetate 7:3)

EXAMPLE VIrac-4-(Bromomethyl)-benzenesulphonyl-N-2-(tert-butoxycarbonyl)piperidinide##STR15##

In analogy to the procedure of Example III, 7.4 g (59% of theory) of thetitle compound are obtained from 8.0 g (30 mmol) of the compound fromExample III and 5.5 g (30 mmol) of tert-butyl rac-pipecolate.

R_(f) =0.53 (petroleum ether/ethyl acetate 5:1)

EXAMPLE VII(S)-4-(Bromomethyl)-3-chlorobenzenesulphonyl-N-2-(tertbutoxycarbonyl)pyrrolidinide##STR16##

In analogy to the procedure of Example III, 13.9 g (96% of theory) ofthe title compound are obtained from 10.0 g (33 mmol) of the compoundfrom Example IV and 5.7 g (33 mmol) of S-proline tert-butyl ester.

R_(f) =0.55 (petroleum ether/ethyl acetate 7:3)

EXAMPLE VIIIrac-4-(Bromomethyl)-3-chlorobenzenesulphonyl-N-2-(tertbutoxycarbonyl)piperidinide##STR17##

In analogy to the procedure of Example III, 14.6 g (98% of theory) ofthe title compound are obtained from 10.0 g (33 mmol) of the compoundfrom Example IV and 6.1 g (33 mmol) of tert-butyl rac-pipecolate.

R_(f) =0.6 (petroleum ether/ethyl acetate 7:3)

EXAMPLE IX4-[(2-Butyl-4-chloro-5-formylimidazolyl)methyl]benzenesulphonyl-N-pyrrolidinide##STR18##

1.1 g (6.0 mmol) of 2-butyl-4-chloro-5-formylimidazole are treated in 12ml of dimethylformamide with 180 mg (6.0 mmol) of an 80% strengthdispersion of sodium hydride in mineral oil and the mixture is stirredat 20° C. for 30 min. It is cooled to 0° C. and 1.8 g (6.0 mmol) of thecompound from Example III in 15 ml of DMF are added. The mixture isstirred at 20° C. for 2.5 h and the reaction mixture is poured onto iceand extracted with ethyl acetate (3×50 ml), and the combined organicphases are washed with saturated sodium chloride solution (5×50 ml),dried over MgSO₄ and filtered, and all the volatiles are stripped off invacuo. The crude product is purified by flash chromotography (petroleumether/ethyl acetate 10:1→3:1, 50 μm particle size), and 1.1 g (60% oftheory) of the title compound are obtained.

R_(f) =0.14 (toluene)

EXAMPLE X4-[(2-Butyl-4-chloro-5-formylimidazolyl)methyl]benzenesulphonyl-N-piperidinide##STR19##

In anslogy to the procedure of Example IX, 3.1 g (61% of theory) of thetitle compound are obtained from 3.8 g (12.0 mmol) of the compound fromExample III and 2.2 g of 2-butyl-4-chloro-5-formylimidazole.

R_(f) =0.39 (petroleum ether/ethyl acetate 7:3)

EXAMPLE XI (S)-4-[(2-Butyl-4-chloro-5-formylimidazolyl)methyl]-BENZENESULPHONYL-N-(2-tert-butoxycarbonyl)pyrrolidinide##STR20##

In analogy to the procedure of Example IX, 6.0 g (74% of theory) of thetitle compound are obtained from 9.1 g (23 mmol) of the compound fromExample V and 3.0 g (16 mmol) of 2-butyl-4-chloro-5-formylimidazole.

R_(f) =0.61 (petroleum ether/ethyl acetate 7:3)

EXAMPLE XIIrac-4-[(2-Butyl-4-chloro-5-formylimidazolyl)methyl]-benzenesulphonyl-N-(2-tert-butoxycarbonyl)piperidinide##STR21##

In analogy to the procedure of Example IX, 4.9 g (53% of theory) of thetitle compound are obtained from 7.4 g (18 mmol) of the compound fromExample VI and 3.3 g (18 mmol) of 2-butyl-4-chloro-5-formylimidazole .

R_(f) =0.08 (petroleum ether/ethyl acetate 7:1)

EXAMPLE XIII(S)-4-[(2-Butyl-4-chloro-5-formylimidazolyl)methyl]-3-chlorobenzenesulphonyl-N-(2-tert-butoxycarbonyl)pyrrolidinide##STR22##

In analogy to the procedure of Example IX, 2.7 g (42% theory) of thetitle compound are obtained from 6.6 g (15 mmol) of the compound fromExample VII and 2.2 g (12 mmol) of 2-butyl-4-chloro-5-formylimidazole.

R_(f) =0.75 (dichloromethane/ethylacetate 10:1)

EXAMPLE XIVrac-4-[(2-Butyl-4-chloro-5-formylimidazolyl)methyl]-3-chlorobenzenesulphonyl-N-(2-tert-butoxycarbonyl)piperidinide##STR23##

In analogy to the procedure of Example IX, 2.4 g (26% of theory) of thetitle compound are obtained from 6.8 g (15 mmol) of the compound fromExample VIII and 2.2 g (12 mmol) of 2-butyl-4-chloro-5-formylimidazole.

R_(f) =0.87 (dichloromethane/ethylacetate 10:1)

EXAMPLE XV(S)-4-[(2-Butyl-5-formylimidazolyl)methyl]-3-chloro-benzenesulphonyl-N-(2-tert-butoxycarbonyl)pyrrolidinide##STR24##

4.98 g (9.15 mmol) of the compound from Example XIII are dissolved in100 ml of THF/50 ml of methanol and the solution is hydrogenated at ahydrogen pressure of about 3 bar for 1 h in the presence of 1.24 g (9.15mmol) of sodium acetate trihydrate and 0.5 g of palladium on activecarbon (5% strength). The solution is then filtered off from thecatalyst and concentrated, and the residue is purified on silica gelusing ethyl acetate/petroleum ether (1:1 and 2:1).

Yield: 3.3 g (71% of theory).

R_(f) : 0.18 (ethyl<acetate/petroleum ether=1:1).

EXAMPLE XVI N-Trifluoroacetyl-L-prolinamide ##STR25##

30 g (0,142 mol) of trifluoroacetylproline are initially introduced into150 ml of DMF under protective gas. At -20° C., 142.6 ml (0.1704 mol) of38% strength PPA in ethyl acetate are added. Ammonia is introduced untilthe mixture is saturated, a white precipitate depositing after 30 min.The batch is thawed under a gentle stream of ammonia. The whole reactionmixture is then added to 600 ml of H₂ O and acidified to pH 4 withconcentrated acetic acid. It is extracted 4× by shaking with 200 ml ofmethylene chloride and 3× by shaking with 200 ml of ether. The combinedorganic phases are dried using magnesium sulphate and the solvent isstripped off. The residues are chromatographed together on silica gel 60F254 methylene chloride/methanol (10:1). The fractions containing theproduct are freed from solvent on a rotary evaporator.

17.12 g of the title compound (57% of theory) are obtained;

R_(f) : 0.345 (T/EA/CH₃ COOH) 20:20:1.

EXAMPLE XVII 2-Cyano-N-trifluororacetyl-pyrrolidine ##STR26##

40 g (0.19 mol) of the products from Example XIII and 45 g=46 ml (0.57mol) of pyridine are initially introduced into 300 ml of THF underprotective gas. At 0° C., 48 g=32.25 ml (0.228 mol) of trifluoroaceticanhydride are added. The reaction mixture is stirred for 30 min at 0° C.and for 90 min at room temperature. The batch is then added to 1 l of 1Nhydrochloric acid and extracted 3× by shaking with 200 ml of methylenechloride. The combined organic phases are extracted by shaking with 200ml of saturated NaCl solution and dried over magnesium sulphate. Thesolvent is stripped off and the residue is chromatographed on silica gel60 F254. Petroleum ether/ethyl acetate/acetic acid (1600:200:5). Thefractions containing the products are concentrated. 32.4 g of the titlecompound (88.8% of theory) are obtained.

R_(f) : 0.57 (petroleum ether/ethyl acetate 7:3)

EXAMPLE XVIII 2-Tetrazolyl-N-trifluoroacetyl-pyrrolidine ##STR27##

31.35 g=32.6 ml (0.26 mol) of diethylaluminiumchloride are initiallyintroduced into 65 ml of toluene under protective gas. 29.95 g=34.04 ml(0.26 mol) of trimethylsilyl azide are added at room temperature and themixture is stirred for 10 min at room temperature. 25 g (0.13 mol) ofthe product from Example XIV, dissolved in 65 ml of toluene, are addedat 0° C. The reaction mixture is stirred for 30 min at 0° C., 120 min atroom temperature and 60 min at 40° C. The cooled batch is treated withsaturated potassium fluoride solution until evolution of gas can nolonger be detected.

The reaction mixture is added to 600 ml of H₂ O and acidified to pH 4and extracted 3× with 100 ml of ethyl acetate. The combined organicphases are treated with 50 ml of n-hexane. In order to remove theazides, about 1/3 of the solvent is removed by distillation over adistillation bridge without cooling. The residue is dried over magnesiumsulphate and freed from solvent on a rotary evaporator.

18.54 g of the title compound (60.6% of theory) are obtained.

R_(f) : 0.4 (toluene/ethyl acetate 1:1).

EXAMPLE XIX N-Trifluoroacetyl-2-[N-trityl-tetrazolyl]pyrrolidine##STR28##

16.23 g (0.069 mol) of the product from Example XV and 10.47 g=14.35 ml(0.1035 mol) of triethylamine are initially introduced into 70 ml ofmethylene chloride. 19.83 g (0.069 mol) of triphenylmethyl chloride arethen added. The reaction mixture is stirred for 1.5 h at roomtemperature, diluted with methylene chloride and extracted with pH 5buffer solution (3×50 ml). The organic phase is dried over magnesiumsulphate. The solvent is stripped off on a rotary evaporator. Theresidue is stirred with ether. The resulting crystals are filtered offwith suction and dried.

24.65 g of the title compound (75% of theory) are obtained.

R_(f) : 0.53 (petroleum ether/ethyl acetate 7:3).

EXAMPLE XX 2-(N-Trityl-tetrazolyl)pyrrolidine ##STR29##

24 g (0.05 mol) of the product from Example XVI are initially introducedinto 100 ml of ethanol under protective gas. 2.84 g (0.075 mol) ofsodium borohydride are added in portions at 0° C. The batch is thawedand stirred at room temperature for 1 h. It is treated with 6 ml ofacetic acid and the whole reaction mixture is added to 500 ml of buffersolution pH 9. The batch is extracted with 3×75 ml of methylenechloride. The combined organic phases are dried over magnesium sulphateand freed from solvent on a rotary evaporator. The residue ischromatographed on silica gel 60 F254. Petroleum ether/ethyl acetate(7:3). The corresponding fractions are concentrated and dried.

7.16 g of the title compound (37.5% of theory) are obtained.

R_(f) : 0.22 (ethyl acetate).

EXAMPLE XXI 4-Bromomethyl-3-chloro-benzenesulphonicacid-2-[trityltetrazolyl]pyrrolidinide ##STR30##

In analogy to the procedure of Example III, 6.49 g of the title compoundi(95% of theory) are obtained from 3.19 g (10.5 mmol) of the compoundfrom Example IV and 4 g (10.5 mmol) of the compound from Example XVII.

R.sub. : 0.53 (petroleum ether/ethyl acetate 7:3).

EXAMPLE XXII 4-(Bromomethyl)-3-fluorobenzenesulphochloride ##STR31##

20.9 g (0.1 mol) of 3-fluoro-4-methylbenzenesulphochloride are taken upin 200 ml of carbon tetrachloride and, after addition of 19.6 g (0.11mol) of N-bromosuccinimide and 0.3 g of dibenzoyl peroxide, the mixtureis heated under reflux for 5 h. After cooling, the solids are filteredoff and the filtrate is freed from solvent. Flash chromatographypetroleum ether/toluene (4:1), 50 μm particle size gives 12.4 g (44% oftheory) of the title compound

R_(f) : 0.42 (petroleum ether/toluene 3:1).

EXAMPLE XXIII 4-(Bromomethyl)-3-trifluoromethylbenzenesulphochloride##STR32##

64.6 g (0.25 mol) of 3-trifluoromethyl-4-methylbenzenesulphochloride aretaken up in 500 ml of carbon tetrachloride and, after addition of 44.5 g(0.25 mol) of N-bromosuccinimide and 0.4 g of ABN, the mixture is heatedunder reflux for 24 h. After cooling, the solids are filtered off andthe filtrate is freed from solvent. Flash chromatographypetroleum-ether/toluene (4:1), 50 μm particle size gives 33.9 g (40% oftheory) of the title compound.

R_(f) : 0.41 (petroleum ether/toluene 3:1)

EXAMPLE XXIV(S)-4-(Bromomethyl)-3-fluorobenzenesulphonyl-N-2-(tert-butoxy-carbonyl)pyrrolidinide##STR33##

In analogy to the procedure of Example III, 12.7 g (100% of theory) ofthe title compound are obtained from 8.6 g (30 mmol) of the compoundfrom Example XIX and 5.1 g (30 mmol) of S-proline tert-butyl ester.

R_(f) : 0.57 (petroleum ether/ethyl acetate 7:3).

EXAMPLE XXV (S)-4-(Bromomethy 1)-3-trifluoromethylbenzenesulphonyl-N2-(tert-butoxycarbonyl-pyrrolidinide##STR34##

In analogy to the procedure of Example III, 23.6 g (100% of theory) ofthe title compound are obtained from 16.9 g (50 mmol) of the compoundfrom Example XX and 8.6 g (50 mmol) of S-proline tert-butyl ester.

R_(f) : 0.63 (petroleum ether/ethyl acetate 7:3).

EXAMPLE XXVI (S)-4-carboxy-3-bydroxybenzenesulphonyl-N-2-(tert.-butoxycarbonyl)-pyrrolidinide ##STR35##

Analogously to the method of Example III, 30.0 g (81% of theory) of thetitle compound are obtained from 23.7 g of4-carboxy-3-hydroxybenzenesulphochloride (100 mmol) and 17.1 g (100mmol) of S-proline tert.-butyl ester.

R_(f) : 0.18 (acetone)

EXAMPLE XXVII (S)-4-Benzyloxycarbonyl-3-benzyloxybenzenesulphonic acidN-2-(tert.-butoxy-carbonyl)-pyrrolidinide ##STR36##

28.3 g of K₂ CO₃ (204 mmol) and 25.7 g (150 mmol) of benzyl bromide areadded to 25.3 g (68 mmol) of the compound of Example XXVI dissolved in200 ml of DMF. The reaction mixture is stirred for a further 2 hours at75° C. and cooled. 1 l of water is then added and the mixture isextracted with ethyl acetate (3×400 ml) and the extract washed withwater (5×400 ml), dried over MgSO₄, filtered and all the volatilecomponents are stripped off in vacuo. The product is purified by flashchromatography (petroleum ether/CH₂ Cl₂ 5:1 and petroleum ether/ethylacetate 6:1, particle size: 50μ) and then purified further byrecrystallisation from 600 ml of a solvent mixture (petroleumether/ethyl acetate 6:1). 35.5 g (95% of theory) of the title compoundare obtained.

R_(f) =0.53 (petroleum ether/ethyl acetate 7:3)

EXAMPLE XVIII (S)-4-(Hydroxymethyl)-3-benzyloxybenzenesulphonic acidN-2-(tert.-butoxy-carbonyl)-pyrrolidihide ##STR37##

11.03 g (20 mmol) of the compound of Example XXVII are dissolved in 100ml of diglyme and, after adding 1.51 g (40 mmol) of sodium borohydfideand 1.68 g (40 mmol) of LiCl, the mixture is stirred for 4 hours at 70°C. After cooling, 500 ml of water are added to the reaction mixture,which is then acidified with 1N HCI to a pH of 3. The mixture isextracted with ether (3×300 ml) and the extract is washed with water(6×300 ml), dried over MgSO₄ and the tiltrate freed from the solvent.The residue is chromatographed on silica gel 60 F 254 (petroleumether/ethyl acetate (7:3)). The corresponding fractions are concentratedby evaporation and dried. 5.0 g (56% of theory) of the title compoundare obtained.

R_(f) =0.36 (petroleum ether/ethyl acetate 7:3)

EXAMPLE XXIX (S)-4-(Bromomethyl)-3-benzyloxybenzenesulphonic acidN-2-(tert.-butoxycarbonyl)-pyrrolidinide ##STR38##

2.24 g (5 mmol) of the compound from Example XXVIII are initiallyintroduced into 20 ml of absolute DMF under an inert gas. 2.53 g (6mmol) of triphenylphosphine dibromide are added at 0° C. The reactionmixture is stirred for 1 hour at room temperature. 200 ml of water areadded, the mixture is extracted with ethyl acetate (3×80 ml) and theextract is washed with water (5×60 ml), dried over MgSO₄, filtered andall the volatile components are stripped off in vacuo. The product ispurified by flash chromatography (CH₂ C₁₂, particle size: 50μ) and 2.55g (100% of theory) of the title compound are obtained.

R_(f) =0.56 (petroleum ether/ethyl acetate 7:3)

PREPARATION EXAMPLE Example 1rac-4-{[2-Butyl-4-chloro-5-(3-cyclopentyl-2-methoxycarbonylpropenyl)imidazolyl]methyl}-3-chlorobenzene-sulphonyl-N-(2-tert-butoxycarbonyl)piperidinide##STR39##

375 mg (2.4 mmol) of methyl 3-cyclopentylpropanecarboxylate are added at-78° C. to a solution of 2.56 mmol of lithium diisopropylamide [preparedin situ from 357 μl (2.56 mmol) of N,N-diisopropylamine in 6.6 ml of THFand 1.5 ml (2.88 mmol) of a 15% strength solution of n-butyllithium inhexane] in 8.1 ml of solvent and the mixture is stirred for 30 min. 900mg (1.6 mmol) of the compound from Example XIV dissolved in 6.6 ml ofTHF are then added at this temperature and the mixture is then stirredfor 1 h at 0° C. A solution of 163 μl (1.75 mmol) of acetic anhydrideand 444 μl (3.19 mmol) of triethylamine in 0.5 ml of dichloromethane isadded at 0° C. to the resulting reaction mixture and it is stirred at20° C. for 2.5 h. The reaction mixture is then treated with 20 ml of H₂O and extracted twice with 30 ml of dichloromethane each time. Thecombined organic phases are extracted by shaking with saturated NaHCO₃solution (1×30 ml) and saturated NaCl solution (2×30 ml), dried overMgSO₄ and freed from the solvent. 1.35 g of a crude product areobtained, which is further reacted without further purification. Thecrude product is taken up in 17 ml of toluene, treated with 666 mg (4.4mmol) of DBU and stirred for 8 h at 95° C. After cooling, the solutionis diluted with 400 ml of toluene and extracted by shaking with 1N HCl(2×100 ml) and then with saturated NaCl (1×100 ml), and the organicphase is dried over MgSO₄ and freed from the solvent. The crude product(1.21 g) is purified by chromatography on silica gel (50 μm,dichloromethane/ethyl acetate 20:1→15:1) 341 mg (29.5% of theory) areobtained.

R_(f) =0.80 (d)

Example 2rac-4-{[2-Butyl-4-chloro-5-(3-cyclopentyl-2-methoxycar-bonylprop-1-enyl)imidazolyl]methyl}-3-chlorobenzene-sulphonyl-N-(2-carboxy)piperidinide##STR40##

270 mg (0.41 mmol) of the compound from Example 1 are dissolved in 5mlof dichloromethane and treated at 0° C. with 1 ml of trifluoroaceticacid. The mixture is stirred at 20° C. for 5 h, all the volatiles arestripped off in vacuo and 322 mg of a crude product are obtained, whichis taken up in 200 ml of ether, washed with H₂ O (4×50 ml) and dried(MgSO₄). After stripping off the solvent, 229 mg (87%; 25.9% over allsteps) of the title compound are obtained.

R_(f) =0.66 (f)

EXAMPLE 3 rac-4-{[2-Butyl-4-chloro-5-(3-cyclopentyl-2-carboxyprop1-enyl)imidazolyl]methyl}-3-chlorobenzenesulphonyl-N-(2carboxy)piperidinide##STR41##

160 mg (0.25 mmol) of the compound from Example 2 are dissolved in amixture of 1 ml of THF, 1 ml of H₂ O and 50 μl of methanol and treatedwith 64 mg (1.5 mmol) of lithium hydroxide. The mixture is stirred at20° C. for 10 h, all the volatiles are stripped off and the residue istaken up in 20 ml of H₂ O and 20 ml of ethyl acetate. The solution isacidified with acetic acid (pH=3), the phases are separated and theaqueous phase is extracted once more with 40 ml of ethyl acetate. Thecombined organic phases are washed eight times with 20 ml of H₂ O eachtime, then once with saturated NaCl solution and dried over MgSO₄. 154mg (99%, 25.5% over all steps) of the title compound are obtained.

The compounds shown in Tables 1 and 2 were prepared in analogy to theprocedures for the compounds of Examples 1-3.

                                      TABLE 1                                     __________________________________________________________________________     ##STR42##                                                                    Ex. No.                                                                            n R.sup.3                                                                             R.sup.4'                                                                           R.sup.5                                                                          m D       Config.                                                                           R.sub.f *                                                                         Yield [%]                              __________________________________________________________________________     4   0 H     C.sub.2 H.sub.5                                                                    H  2 H       --  0.74.sup.a                                                                        30                                      5   0 H     C.sub.2 H.sub.5                                                                    H  1 H       --  0.71.sup.a                                                                        54.7                                    6   0 H     H    H  1 H       --  0.35.sup.a                                                                        36.5                                    7   1                                                                                ##STR43##                                                                          CH.sub.3                                                                           H  2 H       --  0.63.sup.c                                                                        18.5                                    8   1                                                                                ##STR44##                                                                          CH.sub.3                                                                           H  2 H       --  0.54.sup.e                                                                        10.6                                    9   1                                                                                ##STR45##                                                                          H    H  2 H       --  0.51.sup.b                                                                        13.6                                   10   1                                                                                ##STR46##                                                                          H    H  2 H       --  0.56.sup.b                                                                        2.0                                    11   1                                                                                ##STR47##                                                                          CH.sub.3                                                                           H  2 CO.sub.2 C(CH.sub.3).sub.3                                                            rac 0.8.sup.d                                                                         21.5                                   12   1                                                                                ##STR48##                                                                          CH.sub.3                                                                           H  2 CO.sub.2 C(CH.sub.3).sub.3                                                            rac 0.75.sup.d                                                                        29.2                                   13   1                                                                                ##STR49##                                                                          CH.sub.3                                                                           H  2 CO.sub.2 H                                                                            --  0.11.sup.d                                                                        21.5                                   14   1                                                                                ##STR50##                                                                          CH.sub.3                                                                           Cl 1 CO.sub.2 C(CH.sub.3).sub.3                                                            S   0.78.sup.d                                                                        5.5                                    15   1                                                                                ##STR51##                                                                          CH.sub.3                                                                           H  2 CO.sub.2 H                                                                            rac 0.45.sup.b                                                                        29.2                                   16   1                                                                                ##STR52##                                                                          CH.sub.3                                                                           H  1 CO.sub.2 C(CH.sub.3).sub.3                                                            S   0.74.sup.d                                                                        26.4                                   17   1                                                                                ##STR53##                                                                          CH.sub.3                                                                           Cl 2 CO.sub.2 C(CH.sub.3).sub.3                                                            rac 0.80.sup.d                                                                        29.5                                   18   1                                                                                ##STR54##                                                                          CH.sub.3                                                                           H  1 CO.sub.2 H                                                                            S   0.46.sup.f                                                                        25.0                                   19   1                                                                                ##STR55##                                                                          H    H  1 CO.sub.2 H                                                                            S   0.26.sup.f                                                                        6.3                                    20   1                                                                                ##STR56##                                                                          H    Cl 2 CO.sub.2 H                                                                            rac 0.63.sup.f                                                                        25.5                                   21   1                                                                                ##STR57##                                                                          CH.sub.3                                                                           Cl 2 CO.sub.2 H                                                                            rac 0.66.sup.f                                                                        25.9                                   22   1                                                                                ##STR58##                                                                          H    H  2 CO.sub.2 H                                                                            rac 0.73.sup.b                                                                        19.9                                   23   1                                                                                ##STR59##                                                                          H    H  1 CO.sub.2 H                                                                            S   0.30.sup.f                                                                        24.0                                   24   1                                                                                ##STR60##                                                                          H    Cl 1 CO.sub.2 H                                                                            S   0/45.sup.f                                                                        18.9                                   25   1                                                                                ##STR61##                                                                          CH.sub.3                                                                           Cl 3 CO.sub.2 H                                                                            S                                              __________________________________________________________________________

                  TABLE 2                                                         ______________________________________                                         ##STR62##                                                                    Ex.                                          Yield                            No.   R.sup.4'                                                                              R.sup.5                                                                             m   D         Config.                                                                             R.sub.f *                                                                          [%]                              ______________________________________                                        26    CH.sub.3                                                                              H     1   H         --    0.18.sup.c                                                                         22.7                             27    CH.sub.3                                                                              H     2   H         --    0.46.sup.d                                                                         25.5                             28    H       H     1   H         --    0.38.sup.b                                                                         7.3                              29    H       H     2   H         --    0.47.sup.b                                                                         18.4                             30    CH.sub.3                                                                              H     2   CO.sub.2 C(CH.sub.3).sub.3                                                              rac   0.68.sup.d                                                                         16.5                             31    CH.sub.3                                                                              H     2   CO.sub.2 H                                                                              rac   0.11.sup.d                                                                         10.8                             32    H       Cl    2   CO.sub.2 H                                                                              rac   0.62.sup.f                                                                         16.5                             33    H       H     1   CO.sub.2 H                                                                              S     0.24.sup.f                                                                         4.4                              34    CH.sub.3                                                                              Cl    1   CO.sub.2 H                                                                              S                                           35    H       Cl    1   CO.sub.2 H                                                                              S                                           ______________________________________                                    

General Procedure for the Preparation of the Alkali Metal Salts

One equivalent of the acid is dissolved in a dioxane/water mixture,treated with one equivalent of a, 1N solution of the appropriate alkali,frozen and then lyophilised.

The compounds shown in Table 3 are prepared in analogy to theabovementioned methods:

    ______________________________________                                         ##STR63##                                                                                                            Yield                                 Ex. No.                                                                              R.sup.3       R.sup.4' R.sup.9                                                                           R.sub.f *                                                                           [% of th.]                            ______________________________________                                        36     C.sub.2 H.sub.5                                                                             CH.sub.3 H   0.25.sup.a                                                                          84                                    37     C.sub.2 H.sub.5                                                                             CH.sub.3 Na  n.a.  99.7                                  38     C.sub.2 H.sub.5                                                                             H        H   0.17.sup.a                                                                          71                                    39     C.sub.2 H.sub.5                                                                             Na       Na  n.a.  100                                   40     CH(CH.sub.3).sub.2                                                                          C.sub.2 H.sub.5                                                                        H   0.29.sup.a                                                                          100                                   41     CH(CH.sub.3).sub.2                                                                          C.sub.2 H.sub.5                                                                        Na  n.a.  99.9                                  42     CH(CH.sub.3).sub.2                                                                          H        H   0.18.sup.a                                                                          76                                    43     CH(CH.sub.3).sub.2                                                                          Na       Na  n.a.  99.9                                  44                                                                                    ##STR64##    CH.sub.3 H   0.3.sup.a                                                                           99.6                                  45                                                                                    ##STR65##    CH.sub.3 Na  n.a.  99.8                                  46                                                                                    ##STR66##    H        H   0.21.sup.a                                                                          94                                    47                                                                                    ##STR67##    Na       Na  n.a.  100                                   48                                                                                    ##STR68##    CH.sub.3 H   0.2.sup.a                                                                           100                                   49                                                                                    ##STR69##    CH.sub.3 Na  n.a.  100                                   50                                                                                    ##STR70##    H        H   0.16.sup.a                                                                          34                                    51                                                                                    ##STR71##    Na       Na  n.a.  100                                   52                                                                                    ##STR72##    CH.sub.3 H   0.23.sup.a                                                                          85                                    53                                                                                    ##STR73##    CH.sub.3 Na  n.a.  100                                   54                                                                                    ##STR74##    H        H   0.12.sup.a                                                                          81                                    55                                                                                    ##STR75##    Na       Na  n.a.  99.9                                  56                                                                                    ##STR76##    CH.sub.3 H   0.31.sup.a                                                                          95                                    57                                                                                    ##STR77##    CH.sub.3 Na  n.a.  99.8                                  58                                                                                    ##STR78##    H        H   0.19.sup.a                                                                          98                                    59                                                                                    ##STR79##    Na       Na  n.a.  99.8                                  ______________________________________                                         .sup.a Toluene/methanol/glacial acetic acid = 35:5:1                     

We claim:
 1. An aldehyde of the formula ##STR80## in which R¹ representsstraight-chain or branched alkyl or alkenyl each having up to 8 carbonatoms, each of which is optionally substituted by cycloalkyl having 3 to6 carbon atoms, orrepresents cycloalkyl having 3 to 8 carbon atoms, R²represents hydrogen, halogen or straight-chain or branchedperfluoroalkyl having up to 8 carbon atoms, R⁵ represents hydrogen,halogen or straight-chain or branched alkyl having up to 8 carbon atoms,or represents straight-chain or branched perfluoroalkyl having up to 6carbon atoms, or represents a group of the formula --OX, in which Xdenotes hydrogen, benzyl, a hydroxyl protective group selected from thegroup consisting of benzyloxycarbonyl, methanesulphonyl,toluenesulphonyl, 2-nitrobenzyl, 4-nitrobenzyl,2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert-butoxycarbonYl,allyloxycarbonyl, 4-methoxycarbonyl, acetyl, trichloroacetyl,2,2,2-trichloroethoxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,2-(methylthiomethoxy)ethoxycarbonyl, benzoyl, 4-methylbenzoyl,4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl or 4-methoxybenzoylordenotes straight-chain or branched alkyi having up to 8 carbon atoms Arepresents pyrrolidinyl which is optionally substituted up to 2 times byidentical or different perfluoroalkyl having up to 5 carbon atoms or asalt thereof.
 2. An aldehyde according to claim 1, in whichrepresentsstraight-chain or branched alkyl or alkenyl each having up to 6carbon-atoms, each of which is optionally substituted by cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl, represents cyclopropyl,cyclopentyl or cyelohexyl, R² represents hydrogen, fluorine, chlorine,bromine or straight chain or branched perfluoroalkyl having up to 6carbon atoms, R₅ represents hydrogen, fluorine, chlorine, bromine,straight-chain or branched alkyl having up to 6 carbon atoms,orrepresents straight-chain or branched perfluoroalkyl having up to 4carbon atoms, or represents a group of the formula --OX, in whichXdenotes hydrogen, benzyl, acetyl or straight-chain or branched alkylwith up to 6 carbon atoms A represents pyrrolidinyl which is optionallysubstituted by trifluoromethyl or a salt thereof.
 3. An aldehydeaccording to claim 1, in whichR¹ represents straight-chain or branchedalkyl or alkenyl each having up to 4 carbon atoms, or cyclopropyl, R²represents hydrogen, fluorine, chlorine, or straight-chain or branchedperfluoroalkyl having up to 4 carbon atoms, R⁵ represents hydrogen,fluorine, chlorine or straight-chain or branched alkyl having up to 4carbon atoms, orrepresents straight-chain or branched perfluoroalkylhaving up to 3 carbon atoms, or represents a group of the formula --OX,in whichX denotes hydrogen, benzyl, acetyl or straight-chain or branchedalkyl with up to 6 carbon atoms, A represents pyrrolidinyl bonded viathe nitrogen atom, which is optionally substituted by trifluoromethyl ora salt thereof.